Assi Mohamad, Kenawi Moussa, Ropars Mickaël, Rébillard Amélie
EA1274 Laboratory "Movement, Sport and Health Sciences" M2S, University of Rennes 2-ENS Rennes, 35170 Bruz, France.
EA1274 Laboratory "Movement, Sport and Health Sciences" M2S, University of Rennes 2-ENS Rennes, 35170 Bruz, France; Orthopedic and Trauma Surgery Unit-HUGORTHO Pontchaillou University Hospital, 35033 Rennes, France.
Biochem Biophys Res Commun. 2017 Aug 26;490(3):1026-1032. doi: 10.1016/j.bbrc.2017.06.158. Epub 2017 Jun 28.
IL-6 is an axial cytokine overexpressed in cancer to promote growth and increase resistance to anti-cancer therapies. As the application of IL-6-targeting therapies are still limited, alternative non-aggressive and adjuvant approaches, like physical activity (PA) could be useful to reverse IL-6 effects. To get more insights into liposarcoma (LS) pathophysiology, we investigated potential molecular links between IL-6 and LS growth and we tested the impact of PA on such mechanism in an orthotopic model of intramuscular LS. Initially active nude mice have received an intramuscular injection of either human SW872 cells or vehicle, then were respectively randomized into voluntary-active or inactive mice with open or restricted access to activity-wheels. We found that LS-bearing mice exhibited ∼6 fold increase in circulating IL-6 comparing to controls, with a concomitant decrease in hepatic drug-metabolizing enzymes expression. Circulating IL-6 levels were positively correlated with intra-tumor IL-6 expression (r = 0.85, P < 0.01). Interestingly, intra-tumor IL-6, C/EBP-α/β and PPAR-γ expression were correlated together and with greater tumor mass and autophagy markers, notably, GABARAPL-1. Intriguingly, we found that maintaining a spontaneous PA after tumor injection did not reduce the levels of IL-6, but even enhanced tumor growth, induced body weight loss and increased the risk of developing lung metastasis. Our findings suggest that (1) IL-6, C/EBP-β and PPAR-γ exert a potential role in promoting growth of dedifferentiated LS and (2) that PA failed to mechanistically interfere with these factors, but enhanced LS growth via other independent-mechanisms. The preclinical data reported here could be helpful in the sub-molecular classification of LS patients to improve diagnosis and design a low-risk treatment. Circulating IL-6 could serve as an indicator for treatment follow-up and, perhaps, for infra-radiologic LS relapses.
白细胞介素-6是一种在癌症中过度表达的轴性细胞因子，可促进肿瘤生长并增强对抗癌治疗的抗性。由于针对白细胞介素-6的治疗方法应用仍然有限，替代性的非侵袭性辅助方法，如体育活动（PA）可能有助于逆转白细胞介素-6的作用。为了更深入了解脂肪肉瘤（LS）的病理生理学，我们研究了白细胞介素-6与LS生长之间潜在的分子联系，并在肌肉内LS原位模型中测试了体育活动对此类机制的影响。最初活跃的裸鼠接受了人SW872细胞或赋形剂的肌肉注射，然后分别随机分为可自由使用或限制使用活动轮的自愿活动或不活动小鼠。我们发现，与对照组相比，荷LS小鼠循环白细胞介素-6水平增加了约6倍，同时肝脏药物代谢酶表达下降。循环白细胞介素-6水平与肿瘤内白细胞介素-6表达呈正相关（r = 0.85，P < 0.01）。有趣的是，肿瘤内白细胞介素-6、C/EBP-α/β和PPAR-γ表达相互关联，且与更大的肿瘤质量和自噬标志物（特别是GABARAPL-1）相关。有趣的是，我们发现肿瘤注射后维持自发体育活动并没有降低白细胞介素-6水平，反而促进了肿瘤生长，导致体重减轻并增加了发生肺转移的风险。我们的研究结果表明：（1）白细胞介素-6、C/EBP-β和PPAR-γ在促进去分化LS生长中发挥潜在作用；（2）体育活动未能从机制上干扰这些因素，而是通过其他独立机制促进了LS生长。此处报告的临床前数据可能有助于对LS患者进行亚分子分类，以改善诊断并设计低风险治疗方案。循环白细胞介素-6可作为治疗随访指标，或许还可用于影像学下LS复发的监测。
